1. Field of the Invention
The invention relates to antibodies directed against the CD28 lymphocyte receptor and to their fragments, and to their therapeutic uses, in particular in the context of regulating T cell activation.
2. Description of the Related Art
Abnormal activation of T cells is involved in the pathogenesis of many autoimmune diseases, and also in transplant rejection phenomena, where they cause an immune response directed against the transplanted organ to develop.
T lymphocyte activation requires an activating signal, induced by the recognition, by T receptors (TCRs) of the antigen associated with the class II major histocompatibility complex (MHC) and presented by antigen-presenting cells (APCs). However, this activation only causes proliferation of T cells and secretion of specific immunomodulatory cytokines (such as interleukin 2, gamma interferon or interleukin 4) if other T co-stimulation systems are also activated.
One of the most important systems for regulating T lymphocyte activation is the molecular system B7/CD28/CTLA4. This system plays, for example, an essential role in the mechanisms of transplant rejection [Woodward et al., Transplantation, 66, 14-20, (1998)]. The molecules B7.1 (CD80) and B7.2 (CD86) borne by the APCs can activate the CD28 receptor and also the CTLA4 receptor of T lymphocytes. The activation of CD28 sends the T lymphocyte a positive signal which stimulates the cell; on the other hand, the activation of CTLA4 sends a negative signal which leads to a non-response (anergy) [FALLARINO et al., J. Exp. Med., 188, 205-210, (1998)].
Dormant T lymphocytes express a large amount of CD28 and very little CTLA4. When there is a first cognitive contact between an APC and a T lymphocyte, the CD28/B7 interaction is favored, which activates the cell. It is only several hours after the initiation of activation that, due to the increase in membrane expression of CTLA4, the affinity of which for B7 is 5 to 10 times greater than that of CD28, the B7/CD28 interaction shifts in favor of a B7/CTLA4 interaction.
Currently, cyclosporin is mainly used to block T lymphocyte activation, in particular in the context of organ transplants. Despite the effectiveness of this medicinal product, it does not, however, confer absolute protection. In addition, it acts by blocking all the calcium-dependent cell activation pathways, and therefore has a biological activity which is not strictly T lyphocyte specific and leads to a considerable number of side effects. It is therefore desirable to develop new immunosuppressants which have a defined method of action and greater specificity.
It has been postulated that selective inhibition of the agonist signal given to the T cell by CD28, leaving the antagonist system consisting of the pair CTLA4/B7 intact, via specific blocking of the CD28/B7 interaction, would make it possible to prevent T lymphocyte activation. Such specific blocking of the CD28/B7 interaction can be obtained using an antibody directed against CD28.